The invention relates to the treatment of respiratory diseases.
There is significant difficulty in the treatment of young children, including infants, who suffer from respiratory diseases, e.g., asthma. In light of the requirement for frequent and repeated administration of appropriate drugs, issues of compliance and convenience are major aspects of this problem. Furthermore, current methods of intrapulmonary delivery of drugs, e.g., glucocorticosteroids (GCS), are not optimal for use in infants and young children.
The invention provides a new method of treating respiratory diseases such as asthma that involves administering a budesonide composition with a nebulizer not more than once per day. This administration regimen improves compliance and convenience, both significant factors in treating these diseases, particularly in infants and young children. Moreover, the nebulizer is readily and effectively used with infants as well as young children.
Specifically, the invention features a method of treating a patient suffering from a respiratory disease in which a composition, e.g., a suspension, of budesonide is administered by nebulization at a frequency of between once per day and once per month in a continuing regimen. For example, the frequency of administration can be once and only once per day, or once and only once every two days. The doses can be, e.g., 0.05 mg to 15 mg, 0.1 mg to 2.0 mg, or 0.25 mg to 1.0 mg budesonide. The drug can be provided as an aqueous suspension in which the budesonide is suspended in a solvent containing about 0.05 mg to 0.15 mg sodium edetate, about 8.0 mg to 9.0 mg sodium chloride, about 0.15 mg to 0.25 mg polysorbate, about 0.25 mg to 0.30 mg anhydrous citric acid, and about 0.45 mg to 0.55 mg sodium citrate per 1 ml of water.
This new method of treatment can be used in patients suffering from respiratory diseases that include, for example, inflammatory airway diseases, croup, and bronchopulmonary dysplasia. Inflammatory airway diseases include asthma, chronic obstructive pulmonary disease (COPD), and bronchiolitis. Patients can be any age from birth, e.g., newborn, one day to fifteen years old, one month to eight years old, or six months to five years old. The method is also effective in older patients.
A xe2x80x9ccontinuing regimen,xe2x80x9d is a treatment regimen of a series of two or more administrations that occur over days, weeks, months, or years. The dosage of each administration can be the same or varied throughout the continuing regimen.
The doses of budesonide specified for administration by nebulization are those added to the nebulizing device. In a typical situation, approximately 40% to 60% of the drug actually leaves the nebulizer, and of this only approximately 25% (i.e., 10% to 15% of the nominal dose) is delivered to the patient. This is because the drug is delivered constantly, and when the patient is exhaling, the drug leaving the nebulizer will not be delivered to the patient; it will instead be lost to the environment. Of the amount delivered to the patient, approximately 6% to 9% of the nominal dose is delivered to the lungs.
The invention also features a kit for treating respiratory diseases, the kit including a budesonide composition in a sealed container, the composition including 0.05 mg to 15 mg budesonide and a solvent, and a label indicating administration by nebulization in a continuing regimen at a frequency of not more than once per day.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention, e.g., treatment of childhood asthma, will be apparent from the following description and from the claims.
The invention is a convenient yet highly effective method of treating asthma involving not more than one administration per day in a continuing dosage regimen. This new method represents a significant advantage, particularly in infants and young children in which it is frequently difficult to achieve compliance with treatments involving more frequent administrations. Such treatments can involve the use of portable propellant-based inhalers which a young child can either use improperly, lose, or be embarrassed to use in front of his or her peers. Once a day or less frequent treatments are cost effective and result in an improved quality of life. In general, a patient (or a patient""s family) can choose a time of administration that is convenient for them.
In infants, standard inhalation devices are technically difficult to use. The fact that in the new method the drug can be delivered by a mask applied over the infant""s nose and mouth obviates this problem. In addition, in using the nebulizer for administration, the drug is constantly pumped into the face mask. Thus, effective drug delivery does not require constant and deep inhalation. This aspect of the treatment is also advantageous in, for example, incapacitated or neurologically impaired patients.
Two randomized, double-blind, placebo-controlled, twelve-week studies assessed the efficacy and safety of budesonide in children six months to eight years of age who had persistent asthma that was not effectively controlled by non-GCS therapies. The budesonide suspended in a solvent (or a placebo) was administered once per day by a nebulizer connected to a compressor. This treatment resulted in statistically significant improvements in asthma symptoms and a decrease in the number of days in which auxiliary bronchodilator medication was used. Furthermore, there were no significant differences between treatment groups in the type, incidence, or severity of adverse events. There were also no apparent differences between the groups in changes observed in physical examinations, clinical laboratory tests, or oropharyngeal or nasal fungal cultures. Measurement of adrenocorticotropic hormone (ACTH)-induced plasma cortisol levels showed no evidence of hypothalamus-pituitary-adrenal (HPA)-axis suppression by budesonide after twelve weeks of treatment. In summary, these results demonstrated both the efficacy and safety of budesonide when administered to children once per day.
After it has been taken up by airway cells, budesonide forms conjugates (esters) with long-chain fatty acids such as oleic acid. Unlike free budesonide, the budesonide conjugates are inactive as they do not bind to the GCS receptor. However, the conjugation of budesonide is a reversible process. As the concentration of free budesonide in the airway cells falls, the conjugates undergo lipolysis, and further free budesonide is produced, thus maintaining the level available for receptor binding. Intracellular conjugated budesonide thus acts as a xe2x80x9cdepotxe2x80x9d of free budesonide in the airway cells, prolonging the local effect of the compound. This proposed mechanism of action is exemplary; the invention is not limited by any particular mechanism of action.
Methods of Treating Respiratory Diseases
The invention features a new method for treating a patient suffering from a respiratory disease using the drug budesonide which is administered to the patient not more frequently than once per day. It can be delivered, for example, once a day, once every 1.5 days, once every 2 days, once every 3 days, once a week, once every two weeks, or once a month. Treatment is in a continuing regimen for as long as required.
The drug can be delivered dispersed in a solvent, e.g., in the form of a solution or a suspension. It can be suspended in an appropriate physiological solution, e.g., physiological saline or a buffered solution containing 0.05 mg to 0.15 mg disodium edetate, 8.0 mg to 9.0 mg NaCl, 0.15 mg to 0.25 mg polysorbate, 0.25 mg to 0.30 mg anhydrous citric acid, and 0.45 mg to 0.55 mg sodium citrate per 1 ml of water so as to achieve a pH of about 4.0 to 5.0. The budesonide suspension can made, for example, from micronized budesonide.
The therapeutic suspensions can also contain one or more excipients. Excipients are well known in the art and include buffers (e.g., citrate buffer, phosphate buffer, acetate buffer and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (e.g., serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, and glycerol. Solutions or suspensions can be encapsulated in liposomes or biodegradable microspheres.
The budesonide suspension is provided in a substantially sterile form by, for example, dry-heating the budesonide powder for 2 to 6 hours at 90xc2x0 C. to 150xc2x0 C. and employing sterile manufacture for the rest of the process. This involves production and sterilization by filtration of the buffered solvent solution used for the suspension, aseptic suspension of the budesonide in the sterile buffered solvent solution, and dispensing of the suspension into sterile receptacles by methods familiar to those of ordinary skill in the art. This process results in a sterility assurance of 6 as required by the Food and Drug Administration of the U.S. government.
The route of administration is intrapulmonary and the drug is delivered in a nebulized composition by, for example, a nebulizer connected to a compressor (e.g., the Pari LC-Jet Plus(copyright) nebulizer connected to a Pari Master(copyright) compressor manufactured by Pari Respiratory Equipment, Inc., Richmond, Va.).
Patients are those suffering form a respiratory disease. Relevant respiratory diseases include inflammatory airway diseases, croup, and bronchopulmonary dysplasia. Examples of inflammatory airway diseases include asthma, COPD and bronchiolitis.
Patients can be of either sex. They can be treated by the new method at any age from birth. They can, for example be treated as early as thirty minutes after birth. The patients can also much older, e.g., twelve months, two years, four years, then years, forty years, or even seventy years of age, or older. Patients can be six months to five or eight years old.
Doses of budesonide can be the same, or can be varied, for patients of all age groups and all sizes and weights. When administered as a nebulized suspension, the dose can be, e.g., 0.05 mg to 15 mg, 0.1 mg to 2.0 mg, or 0.25 mg to 1.0 mg by budesonide per administration. Evening administration can result in better control of nocturnal and early morning symptoms which are frequent problems in asthma. If excess budesonide is used in a single administration, it is unlikely that harmful effects will occur.
Nebulizable budesonide is provided, for example, as single dose units (e.g., sealed plastic containers or vials) packed in foil envelopes. Each vial contains a unit dose (e.g., 0.25 mg, 0.5 mg, or 1.0 mg) of micronized budesonide suspended in a volume, e.g., 2 ml, of solvent. The unit dose or, if desired and directed by a physician, a fraction of the unit dose is added to the nebulizer. Patients should rinse out their mouths with water after administration of each dose.
Where diseases other than asthma are to be treated with solvent dispersed budesonide, optimal doses can be established by methods familiar to those in the art, e.g., methods analogous to those described in Examples 1 and 2. Doses, for example, for COPD, bronchiolitis, croup, and bronchopulmonary dysplasia, as in asthma, can generally be 0.05 to 15 mg, 0.1 mg to 2.0 mg, or 0.25 mg to 1.0 mg budesonide per administration.